Erythropoietin drives breast cancer progression by activation of its receptor EPOR

Ka Kui Chan, Kyle B Matchett, Jonathan A Coulter, Yuen Hiu-Fung, Cian M McCrudden, Shu-Dong Zhang, Gareth W Irwin, Matthew A. Davidson, Thomas Rülicke, Sophie Schober, Ludger Hengst, Heidelinde Jaekel, Angela Platt-Higgins, Philip S Rudland, Ken I Mills, Perry Maxwell, Mohamed El-Tanani, Terence R Lappin

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Abstract

Breast cancer is a leading cause of cancer-related deaths. Anemia is common in breast cancer patients and can be treated with blood transfusions or with recombinant erythropoietin (EPO) to stimulate red blood cell production. Clinical studies have indicated decreased survival in some groups of cancer patients treated with EPO. Numerous tumor cells express the EPO receptor (EPOR), posing a risk that EPO treatment would enhance tumor growth, but the mechanisms involved in breast tumor progression are poorly understood.Here, we have examined the functional role of the EPO-EPOR axis in pre-clinical models of breast cancer. EPO induced the activation of PI3K/AKT and MAPK pathways in human breast cancer cell lines. EPOR knockdown abrogated human tumor cell growth, induced apoptosis through Bim, reduced invasiveness, and caused downregulation of MYC expression. EPO-induced MYC expression is mediated through the PI3K/AKT and MAPK pathways, and overexpression of MYC partially rescued loss of cell proliferation caused by EPOR downregulation. In a xenotransplantation model, designed to simulate recombinant EPO therapy in breast cancer patients, knockdown of EPOR markedly reduced tumor growth.Thus, our experiments in vitro and in vivo demonstrate that functional EPOR signaling is essential for the tumor-promoting effects of EPO and underline the importance of the EPO-EPOR axis in breast tumor progression.

Original languageEnglish
Pages (from-to)38251-38263
Number of pages13
JournalOncotarget
Volume8
Issue number24
DOIs
Publication statusPublished - 18 Mar 2017

Keywords

  • EPO
  • EPOR
  • breast cancer
  • MYC
  • apoptosis

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    Chan, K. K., Matchett, K. B., Coulter, J. A., Hiu-Fung, Y., McCrudden, C. M., Zhang, S-D., Irwin, G. W., Davidson, M. A., Rülicke, T., Schober, S., Hengst, L., Jaekel, H., Platt-Higgins, A., Rudland, P. S., Mills, K. I., Maxwell, P., El-Tanani, M., & Lappin, T. R. (2017). Erythropoietin drives breast cancer progression by activation of its receptor EPOR. Oncotarget, 8(24), 38251-38263. https://doi.org/10.18632/oncotarget.16368